Activation of seven-transmembrane G-protein coupled receptor (GPCR) mediates extracellular signals into intracellular responses. G-protein coupled receptor 55 (GPR55) is one of GPCRs and activated by endogenous cannabinoids. A family of regulators of G-protein signaling (RGS) stimulates GTP hydrolysis of alpha subunit of G-protein (Gα) and inhibits GPCR/Gα-mediated signaling. RGS2 is member of R4 RGS family and mainly attenuates GPCR/Gα_q signaling. Although RGS2 is known to modulate some GPCR signaling, the specific effects of RGS2 on GPR55-mediated signaling are not fully understood at present. Previously, we reported some RGS proteins interact with protease-activated receptors, one of GPCRs, and modulate their functions. Here, we investigated whether GPR55 interacts with RGS2, employing bioluminescence resonance energy transfer and co-immunoprecipitation analyses. Interestingly, GPR55 interacted with RGS2 alone and also formed a ternary complex with RGS2 and either Gα_q or Gα₁₂. In the presence of GPR55 alone and together with Gα_q or Gα₁₂, RGS2 translocated from the cytoplasm to plasma membrane while RGS1 remained in the cytoplasm. GPR55 activation significantly induced ERK phosphorylation and intracellular calcium mobilization, which were markedly inhibited by RGS2 in HCT116 colon cancer cell line. Furthermore, GPR55-mediated cell proliferation and migration of HCT116 cells, was significantly attenuated by RGS2. Our collective findings highlight a novel physiological function of RGS2, supporting its utility as a therapeutic target to control GPR55-induced pathophysiology.

七跨膜G蛋白偶联受体（GPCR）的激活将细胞外信号介导为细胞内反应。G蛋白偶联受体55（GPR55）是GPCR之一，并被内源性大麻素激活。G蛋白信号转导（RGS）的调节剂家族可刺激G蛋白（Gα）的α亚基的GTP水解，并抑制GPCR /Gα介导的信号转导。RGS2是R4 RGS家族的成员和主要衰减GPCR /Gα _q信号。尽管已知RGS2可以调节某些GPCR信号转导，但目前尚不完全了解RGS2对GPR55介导的信号转导的特异性作用。以前，我们报道了一些RGS蛋白与蛋白酶激活的受体（一种GPCR）相互作用，并调节其功能。在这里，我们利用生物发光共振能量转移和免疫共沉淀分析研究了GPR55是否与RGS2相互作用。有趣的是，单独GPR55相互作用与RGS2和还形成一个三元复合物与RGS2，要么Gα _q或Gα ₁₂。在GPR55的单独和与Gα一起存在_q或Gα ₁₂RGS2从细胞质转移到质膜，而RGS1保留在细胞质中。GPR55激活显着诱导ERK磷酸化和细胞内钙动员，这在HCT116结肠癌细胞系中受到RGS2的显着抑制。此外，RGS2大大减弱了GPR55介导的HCT116细胞的增殖和迁移。我们的集体发现强调了RGS2的新型生理功能，支持其作为控制GPR55诱导的病理生理的治疗靶点的效用。